Coarse-Grained Molecular Simulation of Epidermal Growth Factor Receptor Protein Tyrosine Kinase Multi-Site Self-Phosphorylation
Figure 8
A substrate binding cleft facilitates the cis interaction of the kinase-proximal P-site-992 with the catalytic site.
(A) After docking the P-site-992 peptide (residues 988 to 996) in the catalytic site, the structure of the CT domain sequence between it and the kinase core (residues 968 to 987) was modeled with the program Loopy [18] (see Materials and Methods). The resulting all-atom structure is shown with the solvent accessible surface of PTK domain residues 669 to 967 colored white, modeled CT domain residues 968 to 996 in CPK coloring, and the target Tyr-992 and catalytic Asp-813 residues highlighted in red and green, respectively. The modeled CT domain sequence was found to thread through a cleft between the N- and C-terminal lobes of the PTK domain, suggesting that the presence of this cleft facilitates access in cis of the kinase-proximal P-site-992 to the catalytic site. (B) In simulations of P-site/catalytic site binding events (Fig. 4), the most frequent events (69 of 420) were cis interactions of P-site-992 of the receiver molecule with the catalytic site. Shown here are the final structures from fourteen simulations randomly chosen from those ending with a cis P-site-992 binding event, after alignment of the receiver PTK domain pseudo-atoms 679 to 967 (those of one PTK domain shown as chalk-white beads). The backbone conformations of each of the fourteen CT domain sequences (residues 968 to 996) are shown in different colors, with the target Tyr-992 and catalytic Asp-813 depicted as red and green beads, respectively.